A group of compounds useful in photodynamic therapy, collectively designated green porphyrins, is disclosed in a series of patents including U.S. Pat. Nos. 5,283,255; 4,883,790; 4,920,143; 5,095,030; and 5,171,749, the disclosures of which are incorporated herein by reference. These green porphyrins are prepared using a Diels-Alder reaction with protoporphyrin IX and optional rearrangement or reduction of the resulting product. A particularly preferred form of these green porphyrins, as outlined in the above-referenced patents, is designated a benzoporphyrin derivative in the monoacid form, or "BPD-MA". This drug is currently in clinical trials with respect to photodynamic treatment of various tumors and other conditions.
Photodynamic therapy rests on the assumption that the photoactive compounds administered, in this case the green porphyrins, are without physiological effect in the absence of light. However, when irradiated, the excited forms of the compounds exert local toxic effects. Therefore, for the treatment of tumors, for example, advantage has been taken of the tendency of these photoactive compounds to be retained in tumor tissue after clearance from normal tissue has been effected. It has also been found that local irradiation to areas of neovasculature is effective even before the compounds have been cleared from normal tissue. This "early treatment" is described in copending application Ser. No. 08/391,414, now U.S. Pat. No. 5,705,518 and incorporated herein by reference. However, the timing of treatment in terms of pharmacokinetics has generally been discussed in terms of tumor treatment, and is generally not applicable to use for immunomodulation.
In addition, it is known to apply light to affect cells in the blood stream or elsewhere transcutaneously. U.S. Pat. No. 5,484,804, describes this form of light application which, in regard to tissue targets, can be done after homing of the drug to the target tissue or can be done prior to the opportunity of the drug to home--i.e., before the drug clears normal tissue.
The potential applicability of photodynamic treatment per se to modulating the immune response has been known for some time. For example, Gruner, S. et al. Scand J Immunol (1985) 21:267-273, studied the influence of PDT using hematoporphyrin derivative on murine skin graft survival, epidermal Langerhans cells, and stimulation of the allogeneic mixed leukocyte reaction. As a result of their studies, the authors concluded that hematoporphyrin derivative and visible light interfere with the function of antigen-presenting cells. An additional paper by Gruner, S. et al. Tissue Antigens (1986) 27:147-154, found a similar result when psoralen was used as the photosensitizing agent. A paper by Elmets, C. A. et al. Cancer Res (1986) 46:1608-1611, reports studies using hematoporphyrin derivative in PDT protocols where such PDT protocols were shown to inhibit the delayed-type hypersensitivity or contact hypersensitivity (CHS) reaction in mice using dinitrofluorobenzene (DNFB) as the sensitizing antigen. An immunomodulating effect was found. The authors further note that "mice treated with HPD alone and sensitized to DNFB on the same day "developed a slight but statistically significant (p&lt;0.02) suppression of contact sensitivity." This was said to be considerably less than that obtained using the PDT regimen and the authors hypothesized that "Although HPD alone may be directly immunosuppressive, we cannot exclude the possibility that these might have been inadvertently exposed to small amounts of ambient light that was sufficient to produce mild immunosuppression."
The present applicants, in a report by Simkin, G. et al. Proceedings of "Optical Methods for Tumor Treatment and Detection: Methods and Techniques in Photodynamic Therapy IV" SPIE-The International Society for Optical Engineering, San Jose, Calif., Feb. 4-5, 1995, studied the effect of PDT in the DNFB-based contact hypersensitivity (CHS) model as well as on acceptance of allogeneic skin grafts in mice. The authors found that transdermal PDT effectively inhibited the CHS response against DNFB and was helpful in extending the survival time of skin allografts. Indeed, copending application Ser. No. 08/371,707 which is now abandoned and Ser. No. 08/759,318 which is now U.S. Pat. No. 5,882,328 both incorporated herein by reference, describe the use of photodynamic therapy, including the use of green porphyrins in these regimes to reduce the rejection of allografts. In addition, U.S. Ser. No. 07/889,707, which is now U.S. Pat. No. 5,776,966 and incorporated herein by reference describes the ability of photodynamic therapy using green porphyrins to selectively reduce activated leukocyte cell populations.
U.S. Ser. No. 08/309,509 which is now U.S. Pat. No. 5,807,881 describes the use of photodynamic therapy in treating multiple sclerosis and rheumatoid arthritis as exemplary of autoimmune diseases. In addition, U.S. Pat. No. 5,368,841 describes direct PDT on synovial joints for the same purpose.
The present applicants have also disclosed the effect of PDT using BPD-MA on dendritic cells, which are potent antigen-presenting cells (APC). Treating purified dendritic cells with BPD-MA in vitro in the dark and then exposing these cells to 5 J/cm.sup.2 of 690 nm light resulted in a decrease in expression of MHC Class I and Class II antigens, in expression of ICAM-1 (CD54) and in expression of CD80 and CD86. Expression of leukocyte function associated-1 (LFA-1, CD11a) and the DEC-205 receptor were increased after this treatment while CD45, CD11b (MAC1) and CD18 (integrin .beta.2 chain) were not affected. In addition, dendritic cells treated in this manner were poor stimulators of the allogeneic T cells in a mixed lymphocyte reaction. In the absence of light, there was no effect on the immunostimulatory properties. These results were reported at symposia in Vienna 1996 and San Jose 1997: Hunt, D. W. C. et al., Proceedings of SPIE (1997) 2972:110-121; Proceedings of `Association Internationale de Photobiologie` Vienna, Austria 1996.
Regulating light levels in PDT was studied in connection with the porphyrin precursor ALA by Bae, J. et al. as reported in J Invest Dermatol (1996) 106:950. It was found that low levels of light were effective in enhancing phototoxicity of this precursor compound.
In addition, U.S. Pat. No. 5,422,362, shows the ability of green porphyrins in the absence of light (as opposed to photodynamic treatment) to inhibit restenosis caused by trauma to the blood vessels. The disclosure of this patent is also incorporated herein by reference.
The present applicants have also shown that transcutaneous photodynamic therapy alters the development of murine experimental autoimmune encephalitis (EAE). Leong, S. et al. Photochem Photobiol (1996) 64:751-757.
It has now been found that the green porphyrins have immunomodulatory activity at light levels that correspond to those of ambient light, independent of the more intense light administered either directly to the tissue or transcutaneously. The present invention takes advantage of this property, hitherto unexpected, of the green porphyrins.